Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder
Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder
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DOI：
10.1086/302427
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发表时间：
1999-06-01
影响因子：
9.8
通讯作者：
Lobel, P
中科院分区：
文献类型：
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作者：
Sleat, DE;Gin, RM;Lobel, P
婴儿晚期的神经性脑蜡样脂褐质病（LINCL）是一种进行性和最终致命的儿童期神经退行性疾病。这种遗传性疾病的缺陷基因CLN2编码一种最近发现的溶酶体胃抑素不敏感酸性蛋白酶。为了更好地了解LINCL的分子病理，我们对74个LINCL家族的CLN2进行了遗传调查。在14例患者中，CLN2蛋白酶活性正常，未发现突变，提示其他形式的NCL。在其他60个LINCL家族中，有57个家族鉴定出两种致病等位基因。共有24个突变与LINCL相关，包括6个剪接突变、11个错义突变、3个无义突变、3个小缺失和1个单核苷酸插入。有两种突变特别常见：在115个等位基因中，有38个在3'剪接连接的不变性AG中发现了内含子G- >C转换，在115个等位基因中的32个发现了C- >T转换，在563个中的208个氨基酸上过早终止了翻译。在其他一些最初诊断为青少年NCL的患者中，发现了Arg- >His替代，这与发病年龄较晚和临床表型延长有关。
The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood. The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease. To better understand the molecular pathology of LINCL, we conducted a genetic survey of CLN2 in 74 LINCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic alleles were identified in 57 of the other 60 LINCL families studied. In total, 24 mutations were associated with LINCL, comprising six splice-junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two mutations were particularly common: an intronic G-->C transversion in the invariant AG of a 3' splice junction, found in 38 of 115 alleles, and a C-->T transition in 32 of 115 alleles, which prematurely terminates translation at amino acid 208 of 563. An Arg-->His substitution was identified, which was associated with a late age at onset and protracted clinical phenotype, in a number of other patients originally diagnosed with juvenile NCL.